NLRP1 influences the systemic sclerosis phenotype: a new clue for the contribution of innate immunity in systemic sclerosis-related fibrosing alveolitis pathogenesis

被引：76

作者：

Dieude, P. ^{[1
]}

Guedj, M. ^{[2
]}

Wipff, J. ^{[3
,4
]}

Ruiz, B. ^{[3
]}

Riemekasten, G. ^{[5
]}

Airo, P. ^{[6
]}

Melchers, I. ^{[7
]}

Hachulla, E. ^{[8
]}

Cerinic, M. Matucci ^{[9
]}

Diot, E. ^{[10
]}

Hunzelmann, N. ^{[11
]}

Caramaschi, P. ^{[12
]}

Sibilia, J. ^{[13
]}

Tiev, K. ^{[14
]}

Mouthon, L. ^{[15
]}

Riccieri, V. ^{[16
]}

Cracowski, J. L. ^{[17
]}

Carpentier, P. H. ^{[18
]}

Distler, J. ^{[19
,20
]}

Amoura, Z. ^{[21
]}

Tarner, I. ^{[22
]}

Avouac, J. ^{[3
,4
]}

Meyer, O.

Kahan, A. ^{[4
]}

Boileau, C. ^{[3
,23
]}

Allanore, Y. ^{[3
,4
]}

机构：

[1] Paris Diderot Univ, Dept Rheumatol, Serv Rhumatol, Hop Bichat Claude Bernard,AP HP,INSERM U699, F-75018 Paris, France

[2] Univ Evry Val dEssonne, Lab Stat & Genome, UMR CNRS 8071, INRA 1152, Evry, France

[3] Paris Diderot Univ, Necker Hosp, INSERM U781, F-75018 Paris, France

[4] Paris Descartes Univ, Cochin Hosp, INSERM U1016, Dept Rheumatol A, Paris, France

[5] Charite, Dept Rheumatol & Clin Immunol, Berlin, Germany

[6] Spedali Civil Brescia, I-25125 Brescia, Italy

[7] Univ Med Ctr, Clin Res Unit Rheumatol, Freiburg, Germany

[8] Univ Lille 2, Dept Internal Med, Lille, France

[9] Dept Biomed, Rheumatol Sect, Florence, Italy

[10] CHU Bretonneau, IFR 135, INSERM U618, F-37044 Tours, France

[11] Univ Cologne, Dept Dermatol, D-5000 Cologne, Germany

[12] Univ Verona, Rheumatol Unit, Dept Clin & Expt Med, I-37100 Verona, Italy

[13] Univ Strasbourg, Serv Rhumatol, Hop Hautepierre, Strasbourg, France

[14] Univ Paris 06, St Antoine Hosp, APHP, Paris, France

[15] Paris Descartes Univ, Dept Internal Med, Cochin Hosp, APHP, Paris, France

[16] Univ Roma La Sapienza, Dept Med Clin & Therapy, Div Rheumatol, Rome, Italy

[17] CHU Grenoble, INSERM CIC3, F-38043 Grenoble, France

[18] CHU Grenoble, Clin Univ Med Vasc, F-38043 Grenoble, France

[19] Univ Erlangen Nurnberg, Dept Internal Med 3, Erlangen, Germany

[20] Univ Erlangen Nurnberg, Inst Clin Immunol, Erlangen, Germany

[21] Univ Paris 06, Dept Internal Med 2, Pitie Salpetriere Hosp, APHP, Paris, France

[22] Univ Giessen, Dept Rheumatol & Clin Immunol, Kerckhoff Clin, Bad Nauheim, Germany

[23] St Quentin Yvelines Univ, Lab Biochim Hormonale & Genet, Ambroise Pare Hosp, APHP, Boulogne, France

来源：

ANNALS OF THE RHEUMATIC DISEASES | 2011年 / 70卷 / 04期

关键词：

AUTOIMMUNE ADDISONS-DISEASE; GENETIC RISK-FACTOR; PULMONARY-FIBROSIS; AUTOINFLAMMATORY DISEASES; FUNCTIONAL POLYMORPHISM; INFLAMMATORY CASPASES; SCLERODERMA; INTERLEUKIN-1-BETA; FIBROBLASTS; NALP1;

D O I：

10.1136/ard.2010.131243

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Background Recent evidence has highlighted a potential role of interleukin 1 beta (IL-1 beta) in systemic sclerosis (SSc). NLRP1 provides a scaffold for the assembly of the inflammasome that promotes the processing and maturation of pro-IL-1 beta. In addition, NLRP1 variants were found to confer susceptibility to autoimmune disorders. Objective To study a possible association of the NLRP1 rs6502867, rs2670660 and rs8182352, rs12150220 and rs4790797 with SSc in the European Caucasian population. Methods NLRP1 single nucleotide polymorphisms were genotyped in 3227 individuals comprising a discovery set (870 SSc patients and 962 controls) and a replication set including individuals from Germany (532 SSc patients and 324 controls) and Italy (527 SSc patients and 301 controls), all individuals being of European Caucasian origin. Results Conditional analyses revealed a significant association for the NLRP1 rs8182352 variant with both anti-topoisomerase-positive and SSc-related fibrosing alveolitis (FA) subsets under an additive model: p=0.0042, OR 1.23 (95% CI 1.07 to 1.41) and p=0.0065 OR 1.19 (95% CI 1.05 to 1.36), respectively. Logistic regression analysis showed an additive effect of IRF5 rs2004640, STAT4 rs7574865 and NLRP1 rs8182352 risk alleles on SSc-related FA. Conclusions Our results establish NLRP1 as a new genetic susceptibility factor for SSc-related pulmonary fibrosis and anti-topoisomerase-positive SSc phenotypes. This provides new insights into the pathogenesis of SSc, underlining the potential role of innate immunity in particular in the FA-positive SSc subphenotype, which represents a severe subset of the disease.

引用

页码：668 / 674

页数：7

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